Alzheimer's: Old Drug, New Hope

February 02, 2005

By Catherine Arnst Inflammation is a hallmark of a huge number of illnesses as varied as asthma, Crohn's disease, arteriosclerosis, and Alzheimer's disease. Consequently, researchers have long hoped that the now-controversial COX-2 anti-inflammatory drugs, approved as arthritis treatments, might turn out to be miracle drugs that could fight a range of diseases.

That hope seems likely to die, given the steady buildup of data indicating that the COX-2 drugs increase the risk of heart disease. Merck's (MRK) Vioxx was pulled from the market in September on such evidence, which emerged in a clinical trial of the drug against colon cancer. Similar data, though less definitive, has been reported about Celebrex, a Pfizer (PFE) drug.

The latest reports of heart risks for Celebrex were just made public Jan. 31, although they came from a 1999 study testing the drug against Alzheimer's. That study was doubly disappointing to researchers because it found that Celebrex had no impact on Alzheimer's.

OBSCURE YET INTRIGUING. Little noticed amid the COX-2 controversy, however, was news that a variation of a 20-year-old anti-inflammatory drug has been successful enough against Alzheimer's to warrant accelerated clinical trials. Myriad Genetics (MYGN

announced on Jan. 12 that it's enrolling patients in a Phase 3 trial of Flurizan some nine months ahead of schedule, before it has finished a Phase 2 trial of the drug. This news immediately pushed Myriad's stock price to a 2-1/2 year high of $24.95.

Researchers have speculated for years that anti-inflammatory drugs might be the answer to Alzheimer's. That theory has been bolstered by a number of population studies showing that long-term use of so-called nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen is associated with a reduced risk for the development of Alzheimer's.

Biologically, the link makes sense. Scans of a brain suffering from Alzheimer's disease show dark clumps of plaque scattered throughout the gray matter. These clumps, made from a protein fragment called beta-amyloid, set off inflammation that causes severe damage to the neurons, leading to the dementia and cognitive deterioration that are the hallmarks of the disease.

MORE EFFECTIVE. Flurizan is a surprising candidate because it is a different formulation of flurbiprofen, one of the weakest NSAIDs for relieving arthritis pain. Flurbiprofen is sold in the U.S. under the brand name Ansaid for arthritis, but Ansaid has shown no impact on Alzheimer's disease. Myriad removed two of flurbiprofen's components to create Flurizan, and the new drug does not block the COX enzymes that are targeted by the NSAIDs, as well as by Celebrex and Vioxx. But animal studies have shown that Flurizan does lower the levels of beta-amyloid in the blood more effectively than any of these anti-inflammatories.

"We don't really understand how the drug might work against Alzheimer's," admits Robert C. Green, professor of neurology genetics at Boston University School of Medicine and lead investigator on the Flurizan trial. "What is exciting about this compound is that it is one of the first to be tested in a clinical trial specifically because it might interfere with the creation of beta-amyloid."

The implications about Flurizan go far beyond the fortunes of the Salt Lake City-based biotech company. If it proves effective against Alzheimer's, it might renew interest in seeking a use for other anti-inflammatories, including the COX-2 drugs, against this devastating brain disease.

DESPERATELY NEEDED. So far, though, Flurizan is the only anti-inflammatory shown effective against Alzheimer's, highlighting the great difficulty of coming up with a treatment for the disease. And new treatments are desperately needed. An estimated 4.5 million Americans have Alzheimer's, and the Alzheimer's Assn. predicts that those numbers could reach 16 million by 2050. Just three drugs are now commonly used for the disease, and they offer sufferers only slight relief, usually for a period of months. Patients can live with the disease for up to 20 years, however -- and their care costs the nation some $100 billion a year.

Flurizan's Phase 3 trial, the final phase before an application for approval, will take 12 months and involve approximately 750 patients with mild to moderate Alzheimer's. Myriad says the mid-stage Phase 2 trial will wrap up in March. Both trials are designed to measure any changes in cognitive function and daily living activities. Although far more Alzheimer's trials have failed than succeeded, this one bears watching. Arnst